1. Field of the Invention
The present invention relates to biodegradable homopolymer and block copolymer compositions, in particular those containing both phosphonate and terephthalate ester linkages in the polymer backbone, which degrade in vivo into non-toxic residues. The copolymers of the invention are particularly useful as implantable medical devices and drug delivery systems.
2. Description of the Prior Art
Biocompatible polymeric materials have been used extensively in therapeutic drug delivery and medical implant device applications. Sometimes, it is also desirable for such polymers to be, not only biocompatible, but also biodegradable to obviate the need for removing the polymer once its therapeutic value has been exhausted.
Conventional methods of drug delivery, such as frequent periodic dosing, are not ideal in many cases. For example, with highly toxic drugs, frequent conventional dosing can result in high initial drug levels at the time of dosing, often at near-toxic levels, followed by low drug levels between doses that can be below the level of their therapeutic value. However, with controlled drug delivery, drug levels can be more easily maintained at therapeutic, but non-toxic, levels by controlled release in a predictable manner over a longer term.
If a biodegradable medical device is intended for use as a drug delivery or other controlled-release system, using a polymeric carrier is one effective means to deliver the therapeutic agent locally and in a controlled fashion, see Langer et al., xe2x80x9cChemical and Physical Structures of Polymers as Carriers for Controlled Release of Bioactive Agentsxe2x80x9d, J. Macro. Science, Rev. Macro. Chem. Phys., C23:1, 61-126 (1983). As a result, less total drug is required, and toxic side effects can be minimized. Polymers have been used as carriers of therapeutic agents to effect a localized and sustained release. See Leong et al., xe2x80x9cPolymeric Controlled Drug Deliveryxe2x80x9d, Advanced Drug Delivery Reviews, 1:199-233 (1987) and Langer, xe2x80x9cNew Methods of Drug Deliveryxe2x80x9d, Science, 249:1527-33 (1990); and Chien et al., Novel Drug Delivery Systems (1982). Such delivery systems offer the potential of enhanced therapeutic efficacy and reduced overall toxicity.
For a non-biodegradable matrix, the steps leading to release of the therapeutic agent are water diffusion into the matrix, dissolution of the therapeutic agent, and diffusion of the therapeutic agent out through the channels of the matrix. As a consequence, the mean residence time of the therapeutic agent existing in the soluble state is longer for a non-biodegradable matrix than for a biodegradable matrix, for which passage through the channels of the matrix, while it may occur, is no longer required. Since many pharmaceuticals have short half-lives, therapeutic agents can decompose or become inactivated within the non-biodegradable matrix before they are released.
This issue is particularly significant for many bio-macromolecules and smaller polypeptides, since these molecules are generally hydrolytically unstable and have low permeability through a polymer matrix. In fact, in a non-biodegradable matrix, many bio-macromolecules aggregate and precipitate, blocking the channels necessary for diffusion out of the carrier matrix.
These problems are alleviated by using a biodegradable matrix that, in addition to some diffusion release, also allows controlled release of the therapeutic agent by degradation of the polymer matrix. Examples of classes of synthetic polymers that have been studied as possible biodegradable materials include polyesters (Pitt et al., xe2x80x9cBiodegradable Drug Delivery Systems Based on Alipathic Polyesters: Application to Contraceptives and Narcotic Antagonistsxe2x80x9d, Controlled Release of Bioactive Materials, 19-44 (Richard Baker ed., 1980); poly(amino acids) and pseudo-poly(amino acids) (Pulapura et al., xe2x80x9cTrends in the Development of Bioresorbable Polymers for Medical Applications,xe2x80x9d J. of Biomaterials Appl., 6:1, 216-50 (1992); polyurethanes (Bruin et al., xe2x80x9cBiodegradable Lysine Diisocyanate-based Poly-(Glycolide-co-xcex5 Caprolactone)-Urethane Network in Artificial Skinxe2x80x9d, Biomaterials, 11:4, 291-95 (1990); polyorthoesters (Heller et al., xe2x80x9cRelease of Norethindrone from Poly(Ortho Esters)xe2x80x9d, Polymer Engineering Sci., 21:11, 727-31 (1981); and polyanhydrides (Leong et al., xe2x80x9cPolyanhydrides for Controlled Release of Bioactive Agentsxe2x80x9d, Biomaterials, 7:5, 364-71 (1986).
Specific examples of biodegradable materials that are used as medical implant materials are polylactide, polyglycolide, polydioxanone, poly(lactide-co-glycolide), poly(glycolide-co-polydioxanone), polyanhydrides, poly(glycolide-co-trimethylene carbonate), and poly(glycolide-co-caprolactone). Injectable polyphosphazenes have also been described as useful for forming solid biodegradable implants in situ. See, Dunn et al., in U.S. Pat. Nos. 5,340,849; 5,324,519; 5,278,202; and 5,278,201.
Polymers having phosphoester linkages, called poly(phosphates), poly(phosphonates) and poly(phosphites), are known. See Penczek et al., Handbook of Polymer Synthesis, Chapter 17: xe2x80x9cPhosphorus-Containing Polymersxe2x80x9d, 1077-1132 (Hans R. Kricheldorf ed., 1992). The respective structures of each of these three classes of compounds, each having a different side chain connected to the phosphorus atom, is as follows: 
The versatility of these polymers comes from the versatility of the phosphorus atom, which is known for a multiplicity of reactions. Its bonding can involve the 3p orbitals or various 3s-3p hybrids; spd hybrids are also possible because of the accessible d orbitals. Thus, the physico-chemical properties of the poly(phosphoesters) can be readily changed by varying either the R or Rxe2x80x2 group. The biodegradability of the polymer is due primarily to the physiologically labile phosphoester bond in the backbone of the polymer. By manipulating the backbone or the side chain, a wide range of biodegradation rates are attainable. Kadiyala et al., Biomedical Applications of Synthetic Biodegradable Polymers, Chapter 3: xe2x80x9cPoly(phosphoesters): Synthesis, Physicochemical Characterization and Biological Responsexe2x80x9d, 33-57, 34-5 (Jeffrey O. Hollinger ed., 1995).
An additional feature of poly(phosphoesters) is the availability of functional side groups. Because phosphorus can be pentavalent, drug molecules or other biologically active substances can be chemically linked to the polymer. For example, drugs with xe2x80x94O -carboxy groups may be coupled to the phosphorus via an ester bond, which is hydrolyzable. The Pxe2x80x94Oxe2x80x94C group in the backbone also lowers the glass transition temperature of the polymer and, importantly, confers solubility in common organic solvents, which is desirable for easy characterization and processing. Kadiyala et al. at page 35.
Specifically, EP 386 757 discloses the use of poly(phosphate) esters as prostheses and therapeutic agent delivery vehicles, recognizing that the polymers are biodegradable because of the hydrolyzable phosphoester bond in the backbone. With phosphorous in the trivalent state, the polymers can be polyphosphates or polyphosphonates having the general formula: 
where R and Rxe2x80x2 are organic or organometallic moieties, and n is from about 10 to about 105.
Similarly, EP 057 116 discloses biocompatible polyphosphate esters with difunctional oligomers joined by phosphate bridging structures of general formula I: 
where nxe2x89xa72; OL is an oligomer, preferably chosen from the group compring polyethylene terephthalate and polybutylene terephthalate; Y and Z are the two functional groups of the oligomer, such as OH; and R can be a substituted or unsubstituted alkyl, aryl or aralkyl group. These compounds are described as allowing for easy adjustment of the biodegradability.
Kadiyala et al. specifically discloses reacting bis(2-hydroxyethyl) terephthalate with dimethyl phosphite to form the following biodegradable poly-(phosphite): 
The corresponding terephthalate poly(phosphate) materials have been described as biodegradable materials in copending U.S. patent application Ser. No. 09/053,648 filed Apr. 2, 1998.
Login et al., in U.S. Pat. Nos. 4,259,222; 4,315,847; and 4,315,969, disclose a poly(phosphate)-polyester polymer having a halogenated terephthalate recurring unit useful in flame retardant materials, but without a phosphorus having a side chain.
A number of other U.S. patents disclose poly-(phosphonate) compounds that are useful for their flame retardant qualities, such as Ko et al., U.S. Pat. No. 5,399,654; Besecke et al., U.S. Pat. Nos. 4,463,159 and 4,472,570; Login et al., U.S. Pat. Nos. 4,259,222, 4,315,847, and 4,315,969; Okamato et al., U.S. Pat. Nos. 4,072,658 and 4,156,663; Schmidt et al., U.S. Pat. Nos. 4,328,174 and 4,374,971; and Hechenbleikner, U.S. Pat. No. 4,082,897, or for their soil release effects, such as Engelhardt et al., U.S. Pat. No. 5,530,093. Certain terephthalate poly(phosphonate) compounds are disclosed as flame retardants by Desitter et al., U.S. Pat. No. 3,927,231; Reader, U.S. Pat. No. 3,932,566; and Starck et al., Canadian Patent No. 597,473. However, there still remains a need for further materials that are particularly well-suited for making biodegradable medical devices and drug delivery systems.
Applicants now have discovered that medical devices can be advantageously be made of a composition comprising biodegradable terephthalate polymers comprising the recurring monomeric units shown in formula I: 
wherein
R is a divalent organic moiety;
Rxe2x80x2 is an aliphatic, aromatic or heterocyclic residue;
x is xe2x89xa71; and
n is 3-7,500,
where the biodegradable polymer is sufficiently pure to be biocompatible and is capable of forming biocompatible residues upon biodegradation. Preferably, the device of the invention is adapted for implantation or injection into the body of an animal.
In another embodiment, the invention comprises polymer compositions comprising:
(a) at least one biologically active substance and
(b) a polymer having the recurring monomeric units shown above in formula I.
In a still further embodiment of the invention, a method is provided for the controlled release of a biologically active substance comprising the steps of:
(a) combining the biologically active substance with a biodegradable terephthalate polymer having the recurring monomeric units shown in formula I to form an admixture;
(b) forming the admixture into a shaped, solid article; and
(c) implanting or injecting the solid article in vivo at a preselected site, such that the solid, implanted or injected article is in at least partial contact with a biological fluid.